Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/54595
DC FieldValueLanguage
dc.contributorDepartment of Rehabilitation Sciences-
dc.creatorBehlke, LM-
dc.creatorFoster, RA-
dc.creatorLiu, J-
dc.creatorBenke, D-
dc.creatorBenham, RS-
dc.creatorNathanson, AJ-
dc.creatorYee, BK-
dc.creatorZeilhofer, HU-
dc.creatorEngin, E-
dc.creatorRudolph, U-
dc.date.accessioned2016-08-11T09:37:31Z-
dc.date.available2016-08-11T09:37:31Z-
dc.identifier.issn0893-133Xen_US
dc.identifier.urihttp://hdl.handle.net/10397/54595-
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.titleA pharmacogenetic ‘Restriction-of-function’ approach reveals evidence for anxiolytic-like actions mediated by α5-containing GABAA receptors in miceen_US
dc.typeJournal/Magazine Articleen_US
dc.identifier.spage2492en_US
dc.identifier.epage2501en_US
dc.identifier.volume41en_US
dc.identifier.doi10.1038/npp.2016.49en_US
dcterms.abstractBenzodiazepines have been widely used for their anxiolytic actions. However, the contribution of GABAA receptor subtypes to anxiolysis is still controversial. Studies with mutant mice harboring diazepam-insensitive α-subunits α1, α2, α3, or α5 have revealed that α2-containing GABAA receptors (α2-GABAARs) are required for diazepam-induced anxiolysis, with no evidence for an involvement of any other α-subunit, whereas TP003, described as a selective modulator of α3-containing GABAA receptors, was shown to be anxiolytic. Here, we describe a novel, systematic approach to evaluate the role of positive allosteric modulation of each of the four diazepam-sensitive α-subtypes in anxiety-related behavioral paradigms. By combining H to R point mutations in three out of the four diazepam-sensitive α-subunits in mice with a 129X1/SvJ background, diazepam becomes a subtype-specific modulator of the remaining non-mutated α-subtype. Modulation of α5-GABAARs, but not of α2-GABAARs, increased the time in the light side of the light–dark box as well as open-arm exploration in the elevated plus maze. In contrast, modulation of α3-GABAARs decreased open-arm exploration, whereas modulation of α2-GABAARs increased time in the center in the open-field test. Modulation of any single α-subtype had no effect on stress-induced hyperthermia. Our results provide evidence that modulation of α5-GABAARs elicits anxiolytic-like actions, whereas our data do not provide evidence for an anxiolytic-like action of α3-GABAARs. Thus, α5-GABAARs may be suitable targets for novel anxiolytic drugs.-
dcterms.alternativeA pharmacogenetic ‘Restriction-of-function’ approach reveals evidence for anxiolytic-like actions mediated by α5-containing GABA[sub A] receptors in mice-
dcterms.bibliographicCitationNeuropsychopharmacology, Sept. 2016, v. 41, p. 2492-2501-
dcterms.isPartOfNeuropsychopharmacology-
dcterms.issued2016-9-
dc.identifier.ros2016004226-
dc.identifier.eissn1740-634Xen_US
dc.identifier.rosgroupid2015004253-
dc.description.ros2015-2016 > Academic research: refereed > Publication in refereed journal-
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